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The pulmonary vascular bed in patients with functionally univentricular physiology and a Fontan circulation

Published online by Cambridge University Press:  11 August 2021

Ahmed Krimly ,
C. Charles Jain ,
Alexander Egbe Open the ORCID record for Alexander Egbe [Opens in a new window] ,
Ahmed Alzahrani ,
Khalid Al Najashi ,
Dimpna Albert-Brotons Open the ORCID record for Dimpna Albert-Brotons [Opens in a new window]  and
Gruschen R. Veldtman Open the ORCID record for Gruschen R. Veldtman [Opens in a new window]
Ahmed Krimly
Affiliation:
King Faisal Cardiac Center, National Guard Health Affairs, King Saud bin Abdulaziz University for Health Sciences, Jeddah, Saudi Arabia
C. Charles Jain
Affiliation:
Department of Cardiovascular Medicine, Mayo Clinic, Rochester, MN, USA
Alexander Egbe
Affiliation:
Department of Cardiovascular Medicine, Mayo Clinic, Rochester, MN, USA
Ahmed Alzahrani
Affiliation:
Department of Pediatric Cardiology, Prince Sultan Cardiac Center, Riyadh, Saudi Arabia
Khalid Al Najashi
Affiliation:
Department of Pediatric Cardiology, Prince Sultan Cardiac Center, Riyadh, Saudi Arabia
Dimpna Albert-Brotons
Affiliation:
Heart Centre, King Faisal Specialist Hospital, Riyadh, Saudi Arabia
Gruschen R. Veldtman*
Affiliation:
Scottish Adult Congenital Cardiac Service, Golden Jubilee Hospital, Glasgow, Scotland, UK
*
Author for correspondence: Dr Gruschen R. Veldtman, Scottish Adult Congenital Cardiac Service Golden Jubilee Hospital, Glasgow Agamemnon Street, G81 4DY, Glasgow, UK. Tel: +44(0)1419515390; Fax: +44(0)1419515948. E-mail: Gruschen@me.com
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Abstract

Fontan palliation represents one of the most remarkable surgical advances in the management of individuals born with functionally univentricular physiology. The operation secures adult survival for all but a few with unfavourable anatomy and/or physiology. Inherent to the physiology is passive transpulmonary blood flow, which produces a vulnerability to adequate filling of the systemic ventricle at rest and during exertion. Similarly, the upstream effects of passive flow in the lungs are venous congestion and venous hypertension, especially marked during physical activity. The pulmonary vascular bed has emerged as a defining character on the stage of Fontan circulatory behaviour and clinical outcomes. Its pharmacologic regulation and anatomic rehabilitation therefore seem important strategic therapeutic targets. This review seeks to delineate the important aspects of pulmonary artery development and maturation in functionally univentricular physiology patients, pulmonary artery biology, pulmonary vascular reserve with exercise, and pulmonary artery morphologic and pharmacologic rehabilitation.

Keywords

Fontan operationsingle ventricle physiologypulmonary arteryvascular biologyFontanpulmonary vascular resistancepulmonary vasodilatorstricuspid atresiaFontan procedureheart defectslong-term outcomesuniventricular heartsingle-centre experience

Information

Type
Review
Information
Cardiology in the Young , Volume 31 , Issue 8 , August 2021 , pp. 1241 - 1250
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Copyright
© The Author(s), 2021. Published by Cambridge University Press

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References

Asrani, SK, Asrani, NS, Freese, DK, Phillips, SD, Warnes, CA, Heimbach, J and Kamath, PS Congenital heart disease and the liver. Hepatology 2012; 56: 1160–1169.10.1002/hep.25692CrossRefGoogle ScholarPubMed
Deruiter, MC, Groot, ACG, Rammos, S, Poelmann, RE. The special status of the pulmonary arch artery in the Branchial arch system of the rat. Anat Embryol 1989; 179: 319–325.CrossRefGoogle Scholar
Stenmark, KD, Dempsey, EC, Badesch, DB, Frid, M, Mecham, RP, Parks, WC. Regulation of pulmonary vascular wall cell growth developmental and site-specific heterogeneity. Eur Respir Rev 1993; 3: 629–637.Google Scholar
Hislop, A, Reid, L. Intra-pulmonary arterial development during fetal life-branching pattern and structure. J Anat 1972; 113: 35–48.Google ScholarPubMed
Townsley, MI. Structure and composition of pulmonary arteries, capillaries, and veins. Compr Physiol 2012; 2: 675–709.CrossRefGoogle ScholarPubMed
Davies, P, McBride, J, Murray, GF, Wilcox, BR, Shallal, JA, Reid, L. Structural changes in the canine lung and pulmonary arteries after pneumonectomy. J Appl Physiol Respir Environ Exerc Physiol 1982; 53: 859–864.Google ScholarPubMed
Horsfield, K. Morphometry of the small pulmonary arteries in man. Circ Res 1978; 42: 593–597.CrossRefGoogle ScholarPubMed
von Hayek, H. The Human Lung. Hafner Publishing Co, New York, 1960.Google Scholar
Reid, LM. Structure and function in pulmonary hypertension. New perceptions. Chest 1986; 89: 279–288.CrossRefGoogle ScholarPubMed
Haworth, SG. Physiological society symposium: control of the pulmonary circulation development of the normal and hypertensive pulmonary vasculature. Exp Physiol 1995; 80: 843–853.CrossRefGoogle Scholar
Edvinsson, L, Gulbenkian, S, Wharton, J, Jansen, I, Polak, JM. Peptide-containing nerves in the rat femoral artery and vein. An immunocytochemical and vasomotor study. Blood Vessels 1989; 26: 254–271.Google ScholarPubMed
Chowdhury, UK, Bishnoi, AK, Ray, R, et al. Central pulmonary artery histopathology in patients with cyanotic congenital heart diseases. Ann Thorac Surg 2009; 87: 589–596, 596 e1–3.CrossRefGoogle ScholarPubMed
Trusty, PM, Wei, ZA, Rychik, J, et al. Cardiac magnetic resonance-derived metrics are predictive of liver fibrosis in Fontan patients. Ann Thorac Surg 2020; 109: 1904–1911.CrossRefGoogle ScholarPubMed
Nathan, AS, Loukas, B, Moko, L, et al. Exercise oscillatory ventilation in patients with Fontan physiology. Circ Heart Fail 2015; 8: 304–311.10.1161/CIRCHEARTFAILURE.114.001749CrossRefGoogle ScholarPubMed
Gewillig, M. The Fontan circulation. Heart 2005; 91: 839–846.CrossRefGoogle ScholarPubMed
Gewillig, M, Brown, SC. The Fontan circulation after 45 years: update in physiology. Heart 2016; 102: 1081–1086.CrossRefGoogle ScholarPubMed
Egbe, AC, Connolly, HM, Miranda, WR, et al. Hemodynamics of Fontan Failure: the role of pulmonary vascular disease. Circ Heart Fail 2017; 10: e004515.CrossRefGoogle ScholarPubMed
Choussat, A, Fontan, F, Besse, P. Selection criteria for the Fontan procedure. In: Shinebourne, EA, Anderson, RH (eds.). Paediatric Cardiology. Churchill Livingstone, Edinburgh, Scotland, 1977: 559–566.Google Scholar
Rychik, J, Atz, AM, Celermajer, DS, et al. Evaluation and management of the child and adult with Fontan circulation: a scientific statement from the American Heart Association. Circulation 2019. doi: 10.1161/CIR.0000000000000696.CrossRefGoogle Scholar
Gewillig, M, Brown, SC, Eyskens, B, et al. The Fontan circulation: who controls cardiac output? Interact Cardiovasc Thorac Surg 2010; 10: 428–433.CrossRefGoogle ScholarPubMed
Ridderbos, FS, Bonenkamp, BE, Meyer, SL, et al. Pulmonary artery size is associated with functional clinical status in the Fontan circulation. Heart 2020; 106: 233–239.Google ScholarPubMed
Mitchell, MB, Campbell, DN, Ivy, D, et al. Evidence of pulmonary vascular disease after heart transplantation for Fontan circulation failure. J Thorac Cardiovasc Surg 2004; 128: 693–702.CrossRefGoogle ScholarPubMed
Khambadkone, S, Li, J, de Leval, MR, Cullen, S, Deanfield, JE, Redington, AN. Basal pulmonary vascular resistance and nitric oxide responsiveness late after Fontan-type operation. Circulation 2003; 107: 3204–3208.10.1161/01.CIR.0000074210.49434.40CrossRefGoogle ScholarPubMed
Hakim, TS. Flow-induced release of EDRF in the pulmonary vasculature: site of release and action. Am J Physiol 1994; 267: H363–H369.Google ScholarPubMed
Egbe, AC, Miranda, WR, Anderson, JH, Borlaug, BA. Hemodynamic and clinical implications of impaired pulmonary vascular reserve in the Fontan circulation. J Am Coll Cardiol 2020; 76: 2755–2763.CrossRefGoogle ScholarPubMed
Binotto, MA, Maeda, NY, Lopes, AA. Altered endothelial function following the Fontan procedure. Cardiol Young 2008; 18: 70–74.CrossRefGoogle ScholarPubMed
Zongtao, Y, Huishan, W, Zengwei, W, et al. Experimental study of nonpulsatile flow perfusion and structural remodeling of pulmonary microcirculation vessels. Thorac Cardiovasc Surg 2010; 58: 468–472.CrossRefGoogle ScholarPubMed
Nakano, T, Tominaga, R, Nagano, I, Okabe, H, Yasui, H. Pulsatile flow enhances endothelium-derived nitric oxide release in the peripheral vasculature. Am J Physiol Heart Circ Physiol 2000; 278: H1098–H1104.CrossRefGoogle ScholarPubMed
Latus, H, Lederle, A, Khalil, M, Kerst, G, Schranz, D, Apitz, C. Evaluation of pulmonary endothelial function in Fontan patients. J Thorac Cardiovasc Surg 2019; 158: 523–531 e1.CrossRefGoogle ScholarPubMed
Ridderbos, FJ, Wolff, D, Timmer, A, et al. Adverse pulmonary vascular remodeling in the Fontan circulation. J Heart Lung Transplant 2015; 34: 404–413.CrossRefGoogle ScholarPubMed
Gewillig, M, Cools, B, Van De Bruaene, A. Pulmonary vascular reserve in Fontan patients: looking upstream for the true heart of the matter. J Am Coll Cardiol 2020; 76: 2764–2767.CrossRefGoogle ScholarPubMed
Cai, J, Su, Z, Shi, Z, et al. Nitric oxide and milrinone: combined effect on pulmonary circulation after Fontan-type procedure: a prospective, randomized study. Ann Thorac Surg 2008; 86: 882–888; discussion 882–8.CrossRefGoogle ScholarPubMed
Gamillscheg, A, Zobel, G, Urlesberger, B, et al. Inhaled nitric oxide in patients with critical pulmonary perfusion after Fontan-type procedures and bidirectional Glenn anastomosis. J Thorac Cardiovasc Surg 1997; 113: 435–442.CrossRefGoogle ScholarPubMed
Wolff, D, van Melle, JP, Bartelds, B, et al. Fontan circulation over time. Am J Cardiol 2017; 120: 461–466.CrossRefGoogle ScholarPubMed
Alsaied, T, Sleeper, LA, Masci, M, et al. Maldistribution of pulmonary blood flow in patients after the Fontan operation is associated with worse exercise capacity. J Cardiovasc Magn Reson 2018; 20: 85.CrossRefGoogle ScholarPubMed
Powell, AW, Veldtman, G. Heart rate responses during exercise by dominant ventricle in pediatric and young adult patients with a Fontan circulation. Can J Cardiol 2020; 36: 1508–1515.CrossRefGoogle Scholar
Powell, AW, Chin, C, Alsaied, T, et al. The unique clinical phenotype and exercise Adaptation of Fontan patients with normal exercise capacity. Can J Cardiol 2020; 36: 1499–1507.CrossRefGoogle ScholarPubMed
Claessen, G, La Gerche, A, Van De Bruaene, A, et al. Heart rate reserve in Fontan patients: chronotropic incompetence or hemodynamic limitation? J Am Heart Assoc 2019; 8: e012008.CrossRefGoogle ScholarPubMed
Senzaki, H, Masutani, S, Ishido, H, et al. Cardiac rest and reserve function in patients with Fontan circulation. J Am Coll Cardiol 2006; 47: 2528–2535.CrossRefGoogle ScholarPubMed
Opotowsky, AR, Halpern, D, Kulik, TJ, Systrom, DM, Wu, F. Inadequate venous return as a primary cause for Fontan circulatory limitation. J Heart Lung Transplant 2014; 33: 1194–1196.CrossRefGoogle ScholarPubMed
Budts, W, Ravekes, WJ, Danford, DA, Kutty, S. Diastolic heart failure in patients with the Fontan circulation: a review. JAMA Cardiol 2020; 5: 590–597.CrossRefGoogle ScholarPubMed
Liu, CP, Ting, CT, Yang, TM, et al. Reduced left ventricular compliance in human mitral stenosis. Role of reversible internal constraint. Circulation 1992; 85: 1447–1456.CrossRefGoogle ScholarPubMed
King, G, Ayer, J, Celermajer, D, et al. Atrioventricular valve failure in Fontan palliation. J Am Coll Cardiol 2019; 73: 810–822.CrossRefGoogle ScholarPubMed
Miranda, WR, Hagler, DJ, Taggart, NW, Borlaug, BA, Connolly, HM, Egbe, AC. Elevated ventricular filling pressures and long-term survival in adults post-Fontan. Catheter Cardiovasc Interv 2020; 95: 803–809.CrossRefGoogle ScholarPubMed
Fayyaz, AU, Edwards, WD, Maleszewski, JJ, et al. Global pulmonary vascular remodeling in pulmonary hypertension associated with heart failure and preserved or reduced ejection fraction. Circulation 2018; 137: 1796–1810.CrossRefGoogle ScholarPubMed
Tedford, RJ, Hassoun, PM, Mathai, SC, et al. Pulmonary capillary wedge pressure augments right ventricular pulsatile loading. Circulation 2012; 125: 289–297.CrossRefGoogle ScholarPubMed
Guenette, JA, Ramsook, AH, Dhillon, SS, et al. Ventilatory and sensory responses to incremental exercise in adults with a Fontan circulation. Am J Physiol Heart Circ Physiol 2019; 316: H335–H344.CrossRefGoogle ScholarPubMed
Opotowsky, AR, Landzberg, MJ, Earing, MG, et al. Abnormal spirometry after the Fontan procedure is common and associated with impaired aerobic capacity. Am J Physiol Heart Circ Physiol 2014; 307: H110–H117.CrossRefGoogle ScholarPubMed
Laohachai, K, Winlaw, D, Selvadurai, H, et al. Inspiratory muscle training is associated with improved inspiratory muscle strength, resting cardiac output, and the ventilatory efficiency of exercise in patients with a Fontan circulation. J Am Heart Assoc 2017; 140: e234–e284.Google Scholar
Boutsikou, M, Li, W, Gatzoulis, MA. Non-invasive management of obstructive sleep apnoea in a Fontan patient. Cardiol Young 2019; 29: 977–979.CrossRefGoogle Scholar
Reddy, YNV, Obokata, M, Wiley, B, et al. The haemodynamic basis of lung congestion during exercise in heart failure with preserved ejection fraction. Eur Heart J 2019; 40: 3721–3730.CrossRefGoogle ScholarPubMed
Gordon-Walker, TT, Bove, K, Veldtman, G. Fontan-associated liver disease: a review. J Cardiol 2019; 74: 223–232.CrossRefGoogle ScholarPubMed
Reddy, YNV, Melenovsky, V, Redfield, MM, Nishimura, RA, Borlaug, BA. High-output heart failure: A 15-year experience. J Am Coll Cardiol 2016; 68: 473–482.CrossRefGoogle ScholarPubMed
Mori, M, Hebson, C, Shioda, K, et al. Catheter-measured hemodynamics of adult Fontan circulation: associations with adverse event and end-organ dysfunctions. Congenit Heart Dis 2016; 11: 589–597.CrossRefGoogle ScholarPubMed
Schmitt, B, Steendijk, P, Ovroutski, S, et al. Pulmonary vascular resistance, collateral flow, and ventricular function in patients with a Fontan circulation at rest and during dobutamine stress. Circ Cardiovasc Imaging 2010; 3: 623–631.CrossRefGoogle ScholarPubMed
Ridderbos, FS, Hoendermis, ES, Berger, RMF, van Melle, JP. The Janus-faced Fontan circulation: unravelling its elusive pathophysiology. Eur J Heart Fail 2019; 21: 810–812.CrossRefGoogle ScholarPubMed
Miranda, WR, Borlaug, BA, Hagler, DJ, Connolly, HM, Egbe, AC. Haemodynamic profiles in adult Fontan patients: associated haemodynamics and prognosis. Eur J Heart Fail 2019; 21: 803–809.CrossRefGoogle ScholarPubMed
Ohuchi, H, Miyazaki, A, Negishi, J, et al. Hemodynamic determinants of mortality after Fontan operation. Am Heart J 2017; 189: 9–18.CrossRefGoogle ScholarPubMed
Hebson, CL, McCabe, NM, Elder, RW, et al. Hemodynamic phenotype of the failing Fontan in an adult population. Am J Cardiol 2013; 112: 1943–1947.CrossRefGoogle Scholar
Khairy, P, Fernandes, SM, Mayer, JE Jr, et al. Long-term survival, modes of death, and predictors of mortality in patients with Fontan surgery. Circulation 2008; 117: 85–92.CrossRefGoogle ScholarPubMed
Pundi, KN, Johnson, JN, Dearani, JA, et al. 40-year follow-up after the Fontan operation: long-term outcomes of 1,052 patients. J Am Coll Cardiol 2015; 66: 1700–1710.CrossRefGoogle ScholarPubMed
Egbe, AC, Reddy, YNV, Khan, AR, et al. Venous congestion and pulmonary vascular function in Fontan circulation: implications for prognosis and treatment. Int J Cardiol 2018; 271: 312–316.CrossRefGoogle ScholarPubMed
Yell, J, Boyer, PJ, Bernardi, A, Klewer, S, Seckeler, MD. Improvement in pulmonary vascular resistance after relief of Fontan circuit obstruction. J Invasive Cardiol 2020; 32: E254–E257.Google ScholarPubMed
Egbe, AC, Connolly, HM, Taggart, NW, Al-Otaibi, M, Borlaug, BA. Invasive and noninvasive hemodynamic assessment in adults with Fontan palliation. Int J Cardiol 2018; 254: 96–100.CrossRefGoogle ScholarPubMed
Udholm, S, Aldweib, N, Hjortdal, VE, Veldtman, GR. Prognostic power of cardiopulmonary exercise testing in Fontan patients: a systematic review. Open Heart 2018; 5: e000812.CrossRefGoogle ScholarPubMed
Van De Bruaene, A, La Gerche, A, Claessen, G, et al. Sildenafil improves exercise hemodynamics in Fontan patients. Circ Cardiovasc Imaging 2014; 7: 265–273.CrossRefGoogle ScholarPubMed
Mori, H, Park, IS, Yamagishi, H, et al. Sildenafil reduces pulmonary vascular resistance in single ventricular physiology. Int J Cardiol 2016; 221: 122–127.CrossRefGoogle ScholarPubMed
Agnoletti, G, Gala, S, Ferroni, F, et al. Endothelin inhibitors lower pulmonary vascular resistance and improve functional capacity in patients with Fontan circulation. J Thorac Cardiovasc Surg 2017; 153: 1468–1475.CrossRefGoogle ScholarPubMed
Goldberg, DJ, Zak, V, Goldstein, BH, et al. Results of the FUEL trial. Circulation 2020; 141: 641–651.CrossRefGoogle ScholarPubMed
Day, RW. Acute vasodilator testing following Fontan palliation: an opportunity to guide precision care? Cardiol Young 2020; 30: 829–833.CrossRefGoogle ScholarPubMed
Cedars, AM, Saef, J, Peterson, LR, et al. Effect of Ambrisentan on exercise capacity in adult patients after the Fontan procedure. Am J Cardiol 2016; 117: 1524–1532.CrossRefGoogle ScholarPubMed
Mendoza, A, Albert, L, Belda, S, et al. Pulmonary vasodilator therapy and early postoperative outcome after modified Fontan operation. Cardiol Young 2015; 25: 1136–1140.CrossRefGoogle ScholarPubMed
Goldberg, DJ, French, B, McBride, MG, et al. Impact of oral sildenafil on exercise performance in children and young adults after the fontan operation: a randomized, double-blind, placebo-controlled, crossover trial. Circulation 2011; 123: 1185–1193.CrossRefGoogle Scholar
Giardini, A, Balducci, A, Specchia, S, Gargiulo, G, Bonvicini, M, Picchio, FM. Effect of sildenafil on haemodynamic response to exercise and exercise capacity in Fontan patients. Eur Heart J 2008; 29: 1681–1687.CrossRefGoogle ScholarPubMed
Hebert, A, Mikkelsen, UR, Thilen, U, et al. Bosentan improves exercise capacity in adolescents and adults after Fontan operation: the TEMPO (Treatment with endothelin receptor antagonist in Fontan patients, a randomized, placebo-controlled, double-blind study measuring peak oxygen consumption) study. Circulation 2014; 130: 2021–2030.CrossRefGoogle ScholarPubMed
Shang, XK, Li, YP, Liu, M, et al. Efficacy of endothelin receptor antagonist bosentan on the long-term prognosis in patients after Fontan operation. Zhonghua Xin Xue Guan Bing Za Zhi 2013; 41: 1025–1028.Google ScholarPubMed
Schuuring, MJ, Vis, JC, van Dijk, AP, et al. Impact of Bosentan on exercise capacity in adults after the Fontan procedure: a randomized controlled trial. Eur J Heart Fail 2013; 15: 690–698.CrossRefGoogle ScholarPubMed
Tunks, RD, Barker, PC, Benjamin, DK Jr, et al. Sildenafil exposure and hemodynamic effect after Fontan surgery. Pediatr Crit Care Med 2014; 15: 28–34.CrossRefGoogle ScholarPubMed
Ciliberti, P, Giardini, A. Impact of oral chronic administration of sildenafil in children and young adults after the Fontan operation. Future Cardiol 2011; 7: 609–612.CrossRefGoogle Scholar
Goldberg, DJ, Zak, V, Goldstein, BH, et al. Results of a phase I/II multi-center investigation of Udenafil in adolescents after fontan palliation. Am Heart J 2017; 188: 42–52.10.1016/j.ahj.2017.02.030CrossRefGoogle ScholarPubMed
Cordina, R, Celermajer, DS, d’Udekem, Y. Lower limb exercise generates pulsatile flow into the pulmonary vascular bed in the setting of the Fontan circulation. Cardiol Young 2018; 28: 732–733.CrossRefGoogle ScholarPubMed
Downing, TE, Dori, Y, Harris, MA, Glatz, AC. Left-sided scimitar vein causing cyanosis after Fontan operation: successful transcatheter device occlusion using magnetic resonance imaging X-ray fusion. Congenit Heart Dis 2014; 9: E199–E203.10.1111/chd.12133CrossRefGoogle ScholarPubMed